Oligodendrocytes are the myelin-forming cells of the CNS and are essential for trophic neuronal support. Previous studies suggested that they originate from homogeneous population of lineage restricted progenitors, however several reports have challenged this theory and raised the question of whether distinct populations of progenitors may share a common molecular mechanism of oligodendrocyte differentiation. In this proposal we shall test the hypothesis that all oligodendrocyte progenitors share a common epigenetic mechanism of repression of transcriptional inhibitors of myelin gene expression, neuronal and astrocytic genes that requires histone deacetylation and is necessary for differentiation. According to our model, a common feature of the progenitors is the high levels of inhibitors of myelin gene expression, due to histone acetylation that favors a transcriptionally active conformation of the chromatin in their promoters. As the progenitors begin differentiating, histone deacetylation (mediated by HDACs),.renders the chromatin transcriptionally inactive, decreasing the levels of the inhibitors, and favoring myelin gene expression. Mature Oligodendrocytes further silence the expression of these genes by recruiting proteins that favor chromatin compaction. A similar mechanism is proposed for the repression of neuronal and astrocytic genes. This model is supported by a large amount of preliminary results and our previous studies. The experimental design consists of three aims. Aim 1 tests whether histone deacetylation is part of the common mechanism of differentiation. The other two aims define the role of specific repressive complexes responsible for the repression of transcriptional inhibitors (Aim 2), and of neuronal and astrocytic genes (Aim 3) during oligodendrocyte differentiation. The experiments will be performed in vitro, using cultured progenitors and in vivo, using conditional knockout mice and transplantation studies. This model represents a conceptual advance in the field of developmental neurobiology and, if correct, provides important insights for the development of therapeutic strategies. Therefore this study is highly relevant to public health because it addresses mechanisms that are critical for repair of dysmyelination in infants and demyelination in adults and because of the involvement of defective differentiation of multipotential glial progenitors in the genesis of glioblastomas, the most common and untreatable form of brain tumors.